School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China; Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System (DDS), 138 Xianlin Avenue, Nanjing 210023, China.
School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China; Jiangsu Provincial TCM Engineering Technology Research Center of High Efficient Drug Delivery System (DDS), 138 Xianlin Avenue, Nanjing 210023, China; Department of Pharmacy, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, 157 Daming Avenue, Nanjing 210001, China.
Int J Pharm. 2023 Jun 25;641:123059. doi: 10.1016/j.ijpharm.2023.123059. Epub 2023 May 16.
This paper aimed to improve in vitro dissolution/solubility as well as inhibit intestinal metabolism and thus enhance oral bioavailability for a BDDCS class II drug by constructing surfactant-based amorphous solid dispersions using resveratrol (RES) as a model drug. After preliminary screening of polymers and surfactants, and subsequent prescription optimization, two optimized spray-drying RES-polymer-surfactant ASDs were obtained and exhibited a significant increase in solubility of RES by 2.69-3.45-fold compared to crystalline RES, and by 1.13-1.56-fold compared to corresponding RES-polymer ASDs, maintaining a higher concentration in the dissolution process. A metabolism study using everted sacs showed that two optimized ASDs reduced the concentration ratio of RES-G to RES to 51.66%-52.05% of crystalline RES on the serosal side of the rat everted intestinal sac at 2 h. Consequently, these two RES-polymer-surfactant ASDs achieved significantly higher exposure of RES in the plasma with significant enhancements in C (2.33-2.35-fold higher than crystalline RES, and 1.72-2.04-fold higher than corresponding RES-polymer ASDs), and in AUC (3.51-3.56-fold higher than crystalline RES, and 1.38-1.41-fold higher than corresponding RES-polymer ASDs). These advantages of the RES-polymer-surfactant ASDs in oral absorption of RES were attributed to solubilization by ASDs and metabolic inhibition by UGT inhibitors. The introduction of surfactants including EL and Lab to ASDs plays an important role in inhibiting glucuronidation and further improving solubility. This study demonstrated that such surfactant-based amorphous solid dispersions may serve as a new approach to increase the oral absorption of BDDCS class II drugs.
本文旨在通过构建基于表面活性剂的无定形固体分散体来提高 BDDCS 类 II 药物的体外溶出/溶解度，抑制肠道代谢，从而提高其口服生物利用度，以白藜芦醇（RES）为模型药物。在对聚合物和表面活性剂进行初步筛选，以及随后的处方优化后，得到了两种优化的喷雾干燥 RES-聚合物-表面活性剂 ASD，并显示出 RES 溶解度显著增加，与结晶 RES 相比增加了 2.69-3.45 倍，与相应的 RES-聚合物 ASD 相比增加了 1.13-1.56 倍，在溶解过程中保持更高的浓度。使用外翻囊进行代谢研究表明，两种优化的 ASD 在 2 小时时将 RES-G 与 RES 的浓度比降低至结晶 RES 肠囊浆膜侧的 51.66%-52.05%。因此，这两种 RES-聚合物-表面活性剂 ASD 使 RES 在血浆中的暴露量显著增加，使 C（比结晶 RES 高 2.33-2.35 倍，比相应的 RES-聚合物 ASD 高 1.72-2.04 倍）和 AUC（比结晶 RES 高 3.51-3.56 倍，比相应的 RES-聚合物 ASD 高 1.38-1.41 倍）显著增加。RES-聚合物-表面活性剂 ASD 使 RES 口服吸收具有这些优势，这归因于 ASD 的增溶作用和 UGT 抑制剂的代谢抑制作用。表面活性剂如 EL 和 Lab 的引入到 ASD 中在抑制葡萄糖醛酸化和进一步提高溶解度方面发挥了重要作用。本研究表明，这种基于表面活性剂的无定形固体分散体可能成为提高 BDDCS 类 II 药物口服吸收的新方法。
